The roundworm C. elegans is a simple animal whose nervous system has exactly 302 neurons. Each of the connections between those neurons has been comprehensively mapped, allowing researchers to study how they work together to generate the animal's different behaviors.
Steven Flavell, an MIT associate professor of brain and cognitive sciences and investigator with the Picower Institute for Learning and Memory at MIT and the Howard Hughes Medical Institute, uses the worm as a model to study motivated behaviors such as feeding and navigation, in hopes of shedding light on the fundamental mechanisms that may also determine how similar behaviors are controlled in other animals.
In recent studies, Flavell's lab has uncovered neural mechanisms underlying adaptive changes in the worms' feeding behavior, and his lab has also mapped how the activity of each neuron in the animal's nervous system affects the worms' different behaviors.
Such studies could help researchers gain insight into how brain activity generates behavior in humans. "It is our aim to identify molecular and neural circuit mechanisms that may generalize across organisms," he says, noting that many fundamental biological discoveries, including those related to programmed cell death, microRNA, and RNA interference, were first made in C. elegans.
"Our lab has mostly studied motivated state-dependent behaviors, like feeding and navigation. The machinery that's being used to control these states in C. elegans - for example, neuromodulators - are actually the same as in humans. These pathways are evolutionarily ancient," he says.
Drawn to the lab
Born in London to an English father and a Dutch mother, Flavell came to the United States in 1982 at the age of 2, when his father became chief scientific officer at Biogen. The family lived in Sudbury, Massachusetts, and his mother worked as a computer programmer and math teacher. His father later became a professor of immunology at Yale University.
Though Flavell grew up in a science family, he thought about majoring in English when he arrived at Oberlin College. A musician as well, Flavell took jazz guitar classes at Oberlin's conservatory, and he also plays the piano and the saxophone. However, taking classes in psychology and physiology led him to discover that the field that most captivated him was neuroscience.
"I was immediately sold on neuroscience. It combined the rigor of the biological sciences with deep questions from psychology," he says.
While in college, Flavell worked on a summer research project related to Alzheimer's disease, in a lab at Case Western Reserve University. He then continued the project, which involved analyzing post-mortem Alzheimer's tissue, during his senior year at Oberlin.
"My earliest research revolved around mechanisms of disease. While my research interests have evolved since then, my earliest research experiences were the ones that really got me hooked on working at the bench: running experiments, looking at brand new results, and trying to understand what they mean," he says.
By the end of college, Flavell was a self-described lab rat: "I just love being in the lab." He applied to graduate school and ended up going to Harvard Medical School for a PhD in neuroscience. Working with Michael Greenberg, Flavell studied how sensory experience and resulting neural activity shapes brain development. In particular, he focused on a family of gene regulators called MEF2, which play important roles in neuronal development and synaptic plasticity.
All of that work was done using mouse models, but Flavell transitioned to studying C. elegans during a postdoctoral fellowship working with Cori Bargmann at Rockefeller University. He was interested in studying how neural circuits control behavior, which seemed to be more feasible in simpler animal models.
"Studying how neurons across the brain govern behavior felt like it would be nearly intractable in a large brain - to understand all the nuts and bolts of how neurons interact with each other and ultimately generate behavior seemed daunting," he says. "But I quickly became excited about studying this in C. elegans because at the time it was still the only animal with a full blueprint of its brain: a map of every brain cell and how they are all wired up together."
That wiring diagram includes about 7,000 synapses in the entire nervous system. By comparison, a single human neuron may form more than 10,000 synapses. "Relative to those larger systems, the C. elegans nervous system is mind-bogglingly simple," Flavell says.
Despite their much simpler organization, roundworms can execute complex behaviors such as feeding, locomotion, and egg-laying. They even sleep, form memories, and find suitable mating partners. The neuromodulators and cellular machinery that give rise to those behaviors are similar to those found in humans and other mammals.
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"C. elegans has a fairly well-defined, smallish set of behaviors, which makes it attractive for research. You can really measure almost everything that the animal is doing and study it," Flavell says.
How behavior arises
Early in his career, Flavell's work on C. elegans revealed the neural mechanisms that underlie the animal's stable behavioral states. When worms are foraging for food, they alternate between stably exploring the environment and pausing to feed. "The transition rates between those states really depend on all these cues in the environment. How good is the food environment? How hungry are they? Are there smells indicating a better nearby food source? The animal integrates all of those things and then adjusts their foraging strategy," Flavell says.
These stable behavioral states are controlled by neuromodulators like serotonin. By studying serotonergic regulation of the worm's behavioral states, Flavell's lab has been able to uncover how this important system is organized. In a recent study , Flavell and his colleagues published an "atlas" of the C. elegans serotonin system. They identified every neuron that produces serotonin, every neuron that has serotonin receptors, and how brain activity and behavior change across the animal as serotonin is released.
"Our studies of how the serotonin system works to control behavior have already revealed basic aspects of serotonin signaling that we think ought to generalize all the way up to mammals," Flavell says. "By studying the way that the brain implements these long-lasting states, we can tap into these basic features of neuronal function. With the resolution that you can get studying specific C. elegans neurons and the way that they implement behavior, we can uncover fundamental features of the way that neurons act."
In parallel, Flavell's lab has also been mapping out how neurons across the C. elegans brain control different aspects of behavior. In a 2023 study , Flavell's lab mapped how changes in brain-wide activity relate to behavior. His lab uses special microscopes that can move along with the worms as they explore, allowing them to simultaneously track every behavior and measure the activity of every neuron in the brain. Using these data, the researchers created computational models that can accurately capture the relationship between brain activity and behavior.
This type of research requires expertise in many areas, Flavell says. When looking for faculty jobs, he hoped to find a place where he could collaborate with researchers working in different fields of neuroscience, as well as scientists and engineers from other departments.
"Being at MIT has allowed my lab to be much more multidisciplinary than it could have been elsewhere," he says. "My lab members have had undergrad degrees in physics, math, computer science, biology, neuroscience, and we use tools from all of those disciplines. We engineer microscopes, we build computational models, we come up with molecular tricks to perturb neurons in the C. elegans nervous system. And I think being able to deploy all those kinds of tools leads to exciting research outcomes."
